Boronic acid compound are expected to find use in a variety of medical applications. For example, bortezomib is known as a potent anti-cancer agent that suppresses the growth of myeloma cells by inhibiting the action of an enzyme (proteasome) that degrades unnecessary proteins in cells and by inhibiting the activation of NF-κB. The proteasome is a biological mechanism for degrading structurally abnormal proteins or surplus proteins. Cell growth rate is extremely high in cancer cells as compared to normal cells, and protein synthesis is carried out more actively in cancer cells than in normal cells, resulting in an increased synthesis amount of structurally abnormal proteins as well. Therefore, the function of the proteasome is inhibited by bortezomib and the intracellular concentration of abnormal proteins increases. Further, the activation of NF-κB plays important roles in the survival, growth, and infiltration of tumor cells. NF-κB is generally present as an inactive form while it is bound to its inhibitory protein IκBα. NF-κB is activated by degradation of IκBα by the proteasome. The activation of NF-κB is inhibited by bortezomib inhibiting the function of the proteasome. These phenomena caused by bortezomib can lead to dysfunction and cell death of cancer cells. However, the proteasome is present in normal cells as well, and hence bortezomib has severe side effects. For example, myelosuppression, lung disorder, tumor lysis syndrome, gastrointestinal disorders, peripheral neuropathy, pneumonia, and cardiovascular disorders have been reported as side effects.
The inventors of the present invention have advanced the development of a drug delivery system (DDS) using a polymer micelle from the viewpoint of enhancing the efficacy of a drug while reducing the side effects thereof. One of the goals of the DDS resides in achieving a sustained release of a drug through micelle formation, i.e. the stable retention of a drug in a micelle under physiological conditions, to thereby prevent an abrupt rise in the concentration of the drug in blood and avoid the occurrence of side effects.
However, a polymer micelle capable of sufficiently stably retaining a boronic acid compound such as bortezomib under physiological conditions or a block copolymer suitable for forming the polymer micelle has not yet been achieved. It should be noted that the following references are prior art relating to boronic acid compounds.